Patients with essential hypertension and patients with hypercholesterolemia have reduced endothelium-dependent vasodilator response. This abnormality is related to reduced bioactivity of nitric oxide. Studies in atherosclerotic animals with abnormal endothelial function have shown impaired endothelial regulation of vascular tone due to increased breakdown of nitric oxide by superoxide anions. We therefore hypothesized that a similar mechanism might operate in hypertensive and hypercholesterolemic patients. To this end, we have investigated the effect of superoxide dismutase (a scavenger of superoxide anions) on endothelium-dependent vasodilation. We used native copper-zinc superoxide dismutase (CuZn SOD) which has poor or no intracellular penetrance, thus allowing the study of extracellular breakdown of nitric oxide. Our studies showed that the impaired endothelium-dependent vasodilator responses of hypertensive or hypercholesterolemic patients are not modified by CuZn SOD, thus indicating that extracellular destruction of nitric oxide does not play a significant role in these conditions. An important source of superoxide anions in the intracellular compartment is the xanthine oxidase system. We therefore sought to determine whether an increased production of superoxide anions from this source might contribute to the blunted endothelium-dependent vasodilation. To this end, we studied the effect of oxypurinol (an irreversible inhibitor of xanthine oxidase) on the vascular response to acetylcholine. We observed that oxypurinol induced an augmentation in the response to acetylcholine in hypercholesterolemic patients. These results support the concept that xanthine oxidase-generated superoxide anions might be partly responsible for the impaired endothelial function of patients with hypercholesterolemia. In contrast, we observed no significant modification of endothelium-dependent responses by oxypurinol in hypertensive patients. These latter observations therefore do not support the concept of abnormally increased production of superoxide anions by xanthine oxidase as a mechanism of impaired endothelial vasodilator function in hypertension.